superiority of [68ga]-dotatate pet/ct to other functional imaging … · room 1e-3140, bethesda,...

[68Ga]-DOTATATE in SDHB-related PHEOs/PGLs 1

Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the

localization of SDHB-associated metastatic pheochromocytoma and paraganglioma

Ingo Janssen1,9, Elise M. Blanchet2, Karen Adams1, Clara C. Chen3, Corina M. Millo4, Peter

Herscovitch4, David Taieb5, Electron Kebebew6, Hendrik Lehnert7, Antonio T. Fojo8, and Karel

Pacak1

1Program in Adult and Reproductive Endocrinology, Eunice Kennedy Shriver National Institute

of Child Health and Human Development, National Institutes of Health, 10 Center Dr., Bldg. 10,

Room 1E-3140, Bethesda, MD, 20892

2Nuclear Medicine Department, Bichat Hospital, 46 Rue Henri Huchard, 75018 Paris, France

3Nuclear Medicine Division, Radiology & Imaging Sciences, National Institutes of Health

Clinical Center, 10 Center Dr., Bldg. 10, Room 1C-459, Bethesda, MD, 20892

4Positron Emission Tomography Department, National Institutes of Health Clinical Center,

National Institutes of Health, 10 Center Dr., Bldg. 10, Rooms 1C-401 and 490, Bethesda, MD,

20892

5Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille

University, Marseille, France

6Endocrine Oncology Branch, National Cancer Institute, 10 Center Dr., Bldg. 10, Room 4-5952,

Bethesda, MD, 20892

7Department of Internal Medicine I, University Hospital Schleswig Holstein, Campus Lübeck,

Ratzeburger Allee 160, 23538 Lübeck, Germany

on July 8, 2020. © 2015 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on April 14, 2015; DOI: 10.1158/1078-0432.CCR-14-2751

http://clincancerres.aacrjournals.org/


8Center for Cancer Research, National Cancer Institute, 10 Center Dr., Bldg. 10, Room 12C-103,

Bethesda, MD, 20892

9Department of Radiology and Nuclear Medicine, Section of Nuclear Medicine, University

Hospital Schleswig Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

Running title: [68Ga]-DOTATATE in SDHB-related PHEOs/PGLs

Keywords: [68Ga]-DOTATATE, [18F]-fluoro-2-deoxy-D-glucose, pheochromocytoma,

paraganglioma, metastatic

Financial support: This work was supported, in part, by the Intramural Research Program of the

National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and

Human Development.

Corresponding author:

Karel Pacak, MD, PhD, DSc

Senior Investigator

Chief, Section on Medical Neuroendocrinology

Professor of Medicine

Eunice Kennedy Shriver NICHD, NIH

Building 10, CRC, Room 1E-3140

10 Center Drive MSC-1109

Bethesda, MD, 20892

Phone: (301) 402-4594

Fax: (301) 402-4712

Email: [email protected]

Conflict of interest: The authors claim no conflicts of interest.





Word count: 3567

Total number of figures and tables: 5

Supplemental figure: 1





TRANSLATIONAL RELEVANCE

Patients with succinate dehydrogenase subunit B (SDHB) mutation-related

pheochromocytoma/paraganglioma (PHEO/PGL) are known to suffer from aggressive tumor

behavior that has a very high likelihood of metastasis. This work focuses solely on the

performance of [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) PET/CT in patients

with metastatic SDHB-related PHEOs/PGLs and demonstrates the superiority of [68Ga]-

DOTATATE PET/CT in the detection of metastatic lesions in these patients, compared to all

other and currently recommended functional imaging modalities. Our results may suggest

modifying the functional imaging algorithm for these patients, dependent on the clinical setting,

which currently places [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) PET/CT as the gold

standard. Furthermore, our results indicate that peptide receptor radionuclide therapy or

treatment with so-called “cold” somatostatin receptor analogs, long-awaited remedies, could be

used as new and promising therapeutic options for patients with metastatic SDHB-related

PHEOs/PGLs.





ABSTRACT

Purpose: Patients with succinate dehydrogenase subunit B (SDHB) mutation-related

pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than

other hereditary PHEOs/PGLs. Current therapeutic approaches are limited but the best outcomes

are based on the early and proper detection of as many lesions as possible. Because

PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess

the clinical utility of [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) positron emission

tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison

to the currently recommended functional imaging modalities [18F]-fluorodopamine ([18F]-FDA),

[18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), [18F]-fluoro-2-deoxy-D-glucose ([18F]-

FDG) PET/CT as well as CT/magnetic resonance imaging (MRI).

Experimental Design: [68Ga]-DOTATATE PET/CT was prospectively performed in 17

patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [18F]-FDG

PET/CT and CT/MRI with 16 of the 17 patients also receiving [18F]-FDOPA and [18F]-FDA

PET/CT scans. Detection rates of metastatic lesions were compared between all these functional

imaging studies. A composite synthesis of all used functional and anatomical imaging studies

served as the imaging comparator.

Results: [68Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of

98.6% (95% confidence interval (CI) 96.5% to 99.5%), [18F]-FDG, [18F]-FDOPA, [18F]-FDA

PET/CT, and CT/MRI showed detection rates of 85.8% (CI 81.3% to 89.4%) (p<0.01), 61.4%

(CI 55.6% to 66.9%) (p<0.01), 51.9% (CI 46.1% to 57.7%) (p<0.01), and 84.8% (CI 80.0% to

88.5%) (p<0.01), respectively.





Conclusions: [68Ga]-DOTATATE PET/CT showed a significantly superior detection rate

compared to all other functional and anatomical imaging modalities and may represent the

preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL.





INTRODUCTION

Pheochromocytomas/paragangliomas (PHEOs/PGLs) are tumors derived from

sympathetic tissue in adrenal or extra-adrenal abdominal locations or from parasympathetic

tissue in the thorax or head and neck (1). More than 35% of PHEOs/PGLs are hereditary,

including multiple endocrine neoplasia 2 (MEN2), von Hippel-Lindau syndrome (VHL), and

neurofibromatosis 1 (NF1). In recent years, gene mutations encoding the 4 subunits of the

succinate dehydrogenase (SDH) complex (2, 3), fumarate hydratase (FH) (4), MYC-associated

factor X (MAX) (5), and hypoxia-inducible factor 2α (HIF2A) (6) have been evaluated and often

found to be associated with the presence of multiple and metastatic PHEOs/PGLs.

More than 40% of metastatic PHEOs/PGLs are related to succinate dehydrogenase

subunit B (SDHB) mutation carriers (7), who are at high risk for developing metastatic disease.

Some studies show a risk of up to 90% (8), with an only 36% 5-year probability of survival after

diagnosis of metastatic disease (7). Proper staging and early detection of metastatic disease and

evaluation of the extent of metastatic disease in these high risk patients is crucial and has a major

effect on a patient’s prognosis, including choosing the necessary treatment and follow-up (9).

Current treatment options in metastatic PHEOs/PGLs are limited and consist of

radionuclide therapy with [131I]-metaiodobenzylguanidine (MIBG) and chemotherapy with

cyclophosphamide, vincristine, and dacarbazine (CVD) (10, 11). Surgery and external beam

radiotherapy are less commonly used options in some patients. However, at least 50% of patients

with metastatic PHEOs/PGLs, especially those with SDHB mutations, do not benefit from [131I]-

MIBG treatment due to a lack of the norepinephrine transporter system, resulting in suboptimal

or no [131I]-MIBG-uptake (12). The use of CVD is a good alternative, but is reserved for patients





with rapidly growing tumors or extensive organ tumor burden (especially in the liver) and

limited by treatment-related toxicity. Thus, there is great interest and need to find new means of

therapeutic options, including radionuclide therapy.

PHEOs/PGLs, similar to other neuroendocrine tumors (NETs), are known to express

somatostatin receptors (SSTRs) (13) and new, promising radiolabelled DOTA-peptides for SSTR

imaging and SSTR-targeting treatment have been developed.

Compared to [111In]-DTPA-octreotide (Octreoscan), which is used for SSTR

scintigraphy, the newly developed DOTA-peptides such as DOTA(0)-Tyr(3)-octreotate

(DOTATATE), DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC), and DOTA(1)-Nal(3)-

octreotide (DOTANOC) bind to SSTR expressing tumors much more effectively (14). In

particular, DOTATATE has a very high affinity for SSTR2, (14), which is overexpressed in most

PHEOs/PGLs (13), and has recently been used for their localization (15). Increased expression of

SSTR2A and SSTR3 was recently shown in PHEOs/PGLs with SDH deficiency (16), including

SDHB mutations.

DOTA-peptides can either be labeled with the diagnostic positron emission tomography

(PET) tracer [68Ga] or therapeutic β-emitters like [177Lu] or [90Y]. On one hand, they can provide

sensitive SSTR-imaging, enabling improved anatomic localization using PET/computed

tomography (CT) technique (17) compared to SSTR scintigraphy. On the other hand, when

bound to therapeutic β-emitters, they can and are used for peptide receptor radionuclide therapy

(PRRT) in SSTR overexpressing tumors, especially gastroenteropancreatic NETs (18).

Treatment results in metastatic PHEOs/PGLs are also promising (19).

The present study had two main aims: first, to evaluate [68Ga]-DOTATATE PET/CT in

patients with metastatic SDHB-related PHEOs/PGLs and assess their eligibility for future PRRT





as a new and needed therapeutic approach; and second, to assess the diagnostic value of [68Ga]-

DOTATATE PET/CT in comparison to other well-established and currently recommended

functional imaging studies in PHEOs/PGLs (20), including [18F]-fluorodopamine ([18F]-FDA),

[18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), [18F]-fluoro-2-deoxy-D-glucose ([18F]-

FDG) PET/CT, and in comparison to CT/magnetic resonance imaging (MRI). Because

histological proof was not possible in many metastatic lesions, the composite of both anatomical

and all functional imaging tests was considered the imaging comparator.

PATIENTS AND METHODS

Patients

Between January and December 2014, 17 consecutive patients (11 men, 6 women) with

SDHB mutation-associated PHEOs/PGLs with a mean age of 40.3±14.0 years were prospectively

evaluated at the Eunice Kennedy Shriver National Institute of Child Health and Human

Development (NICHD) at the National Institutes of Health (NIH). All patients had proven

metastatic PHEOs/PGLs based on clinical evaluation, including previously found and surgically

removed PHEOs/PGLs, biochemical diagnosis, and anatomical and functional imaging.

The study protocol was approved by the institutional review board of the Eunice Kennedy

Shriver NICHD (protocol: 00-CH-0093). All patients provided written informed consent for all

clinical, genetic, biochemical, and imaging studies regarding PHEOs/PGLs.

Mean age at diagnosis of primary PHEO/PGL in these patients was 30.2±15.0 years. The

average interval between diagnosis of a primary tumor and referral to the NIH was 4.5±3.8 years.

All 17 patients previously underwent resection of their primary PHEO/PGL. Individual patient

characteristics are summarized in Table 1.





Imaging Techniques

CT scans of the neck, chest, abdomen, and pelvis were performed using the following

devices: Siemens Somatom Definition AS, Siemens Somatom Definition Flash, Siemens

Medical Solutions; Toshiba Aquilion ONE, Toshiba Medical Systems. Section thickness was up

to 3 millimeters (mm) in the neck and 5 mm through the chest, abdomen, and pelvis. All studies

were performed with intravenous (i.v.) rapid infusion of nonionic water-soluble contrast agent as

well as oral contrast material.

MR scans of the neck, chest, abdomen, and pelvis were obtained with 1.5 and 3 Tesla

scanners (Philips Achieva 1.5 and 3 Tesla, Philips Medical Systems; Siemens Verio 1.5 Tesla,

Siemens Medical Solutions). Image thickness was 5 mm for all neck studies and 6 mm for chest,

abdominal, and pelvic scans. Pre- and post-injection images were obtained in the axial plane. All

MR scans included axial T2 series with and without fat saturation, STIR series, and T1 pre- and

post-contrast series. MR scans of the abdomen and pelvis also included axial T1 in and out of

phase and dynamic THRIVE during infusion of contrast, followed by delayed axial and coronal

post-contrast scans after i.v. injection of a gadolinium-diethylenetriamine pentaacetic acid

contrast agent.

All 17 patients underwent [68Ga]-DOTATATE, [18F]-FDG PET/CT scanning, and

CT/MRI, with 16 also receiving [18F]-FDOPA and [18F]-FDA PET/CT scans.

PET/CT scans from the upper thighs to the skull were performed 60 min after i.v.

injection of a mean administered activity of 201.8±39.6 MBq [68Ga]-DOTATATE, 60 min after

362.8±112 MBq [18F]-FDG, 30 min after 458.5±83.1 MBq [18F]-FDOPA, and approximately 8

min after 37.2±1.1 MBq [18F]-FDA. 60 min before each [18F]-FDOPA scan, 200 milligrams (mg)





of carbidopa were administered orally. All PET/CT scans were performed on a Siemens

Biograph-mCT 128 PET/CT scanner (Siemens Medical Solutions). PET imaging was obtained in

3D mode. PET images were reconstructed on a 256 x 256 matrix using an iterative algorithm

provided by the manufacturer, which also uses time of flight (TOF). Low-dose CT studies for

attenuation correction and anatomic co-registration were performed without contrast and used for

anatomical localization only.

Analysis of Data

[68Ga]-DOTATATE PET/CT studies were each read independently by two nuclear

medicine physicians blinded to all imaging and clinical data except for the diagnosis, sex, and

age of the patient.

Maximal standardized uptake values (SUVmax) were determined and focal areas of

abnormal uptake showing a higher SUVmax than surrounding tissue were considered as lesions.

Discrepancies, which occurred in 6 lesions with a mean SUV of 6.2±5.6 in 4 patients, were

solved by consensus review. In all other imaging studies, physicians were blinded to [68Ga]-

DOTATATE PET/CT scans and clinical data except for diagnosis, sex, age of the patient, and

previous imaging studies. All imaging studies were performed within 22±15 days of each other.

For regional analysis, adrenal glands, liver, abdominal/pelvic compartments (excluding adrenal

glands and liver), lungs, mediastinum, and bone were analyzed separately. A patient or region

was considered positive regardless of the number of positive findings. Patient-to-patient, region-

to-region, and lesion-to-lesion analyses were performed. If the number of lesions in a region

exceeded 15, the count was truncated at 15. Patient-, region-, and lesion-related detection rates

were compared. Head and neck PGLs were excluded from the analysis in patients with head and





neck PGLs and sympathetic PGLs.

Histologic proof of metastatic lesions was not feasible. The composite of anatomic and

all performed functional imaging tests was considered the imaging comparator. A positive result

on at least two different functional imaging modalities or at least one functional imaging study

and CT/MRI was counted as true disease, whereas a lesion detected only on CT/MRI or only on

one functional imaging test while negative on all other used imaging tests was considered a

false-positive imaging result.

Statistics

Results are given as means with 95% confidence intervals (CIs) unless stated otherwise.

For statistical analysis, the McNemar test was used to compare sensitivities between [68Ga]-

DOTATATE PET/CT and the other imaging modalities. A two-sided p<0.05 was considered

significant.

RESULTS

[68Ga]-DOTATATE PET/CT had a lesion-based detection rate of 98.6% (CI 96.5% to

99.5%), identifying 285 of 289 lesions (mean SUV 56.0±62.1) compared to our defined imaging

comparator. Significantly more lesions were identified on [68Ga]-DOTATATE PET/CT

compared to all other used functional imaging modalities and CT/MRI (two-sided p<0.01 for

each imaging modality compared to [68Ga]-DOTATATE PET/CT; corresponding cross tables in

Supplemental Figure 1). Lesion-based findings on [68Ga]-DOTATATE PET/CT compared to all

other used functional imaging modalities and CT/MRI are summarized and outlined in Tables 2

and 3 as well as in Figure 1. Metastatic lesions were found in the mediastinum, lungs, liver,





abdomen/pelvis, and bones. Those in the mediastinum, abdomen, or pelvis were located in

lymphatic nodes. Three bone lesions, which were positive on [18F]-FDA and [18F]-FDG PET/CT,

and one lung lesion, which was positive on [18F]-FDG PET/CT and anatomical imaging, were

not identified by [68Ga]-DOTATATE PET/CT. A lesion-based evaluation excluding the patient

who only received [68Ga]-DOTATATE, [18F]-FDG PET/CT, and CT/MRI did not lead to any

statistical change.

Besides the 285 lesions confirmed by the defined imaging comparator, [68Ga]-

DOTATATE PET/CT detected 33 additional lesions: 8 in mediastinal lymphatic nodes, 10 in

retroperitoneal and pelvic lymphatic nodes, and 15 bone lesions (mean SUV 8.2±6.4). All lesions

were in the field of view of CT/MR. In the anatomical imaging studies CT/MRI, 8 lesions were

reported, which were not positive on any functional imaging study. Two were retroperitoneal

lymphatic nodes (1.5 centimeter (cm) and 1.6 cm), 4 were in the lungs (0.4 cm-0.8 cm), and two

in the liver (0.7 cm and 0. 8 cm). Three mediastinal lesions were only positive in [18F]-FDG

PET/CT. Not a single lesion was only positive in either [18F]-FDOPA or [18F]-FDA PET/CT but

not another functional or anatomic imaging test.

Per patient detection rates of [68Ga]-DOTATATE, [18F]-FDG, [18F]-FDOPA, [18F]-FDA

PET/CT and CT/MRI were 100% (17 out of 17 patients (17/17)), CI 81.6% to 100%, 100%

(17/17), CI 81.6% to 100%, 87.5% (14/16), CI 64.0% to 96.5%, 81.3% (13/16), CI 57.0% to

93.4% and 100 % (17/17), CI 81.6% to 100%, respectively.

The per region detection rate for [68Ga]-DOTATATE was 100%, identifying 42 out of 42

regions (42/42), CI 91.6% to 100%, 97.6% for [18F]-FDG (41/42), CI 87.7% to 99.6%, 65.9% for

[18F]-FDOPA (27/41), CI 50.6% to 78.4%, 58.4% for [18F]-FDA PET/CT (24/41), CI 43.4% to

72.2%, and 95.2% for CT/MRI (40/42), CI 84.2% to 98.7%.





A PET-imaging example comparing [68Ga]-DOTATATE, [18F]-FDG, [18F]-FDOPA, and

[18F]-FDA PET/CT is shown in Figure 2.

DISCUSSION

In this study, we evaluated [68Ga]-DOTATATE PET/CT in a cohort of patients with

SDHB-related metastatic PHEOs/PGLs in comparison to [18F]-FDA, [18F]-FDOPA, [18F]-FDG

PET/CT, and CT/MRI. The composite of both anatomical and all functional imaging tests was

considered the imaging comparator.

[68Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% (CI

96.5% to 99.5%), which was significantly superior to all other imaging modalities in this study,

thus demonstrating the utility of this modality in localizing tumors in SDHB-related PHEO/PGL.

We feel this modality will also be useful in determining the possible eligibility for PRRT in

patients with SDHB-related PHEO/PGL.

Functional imaging agents are able to target PHEOs/PGLs through different mechanisms.

[18F]-FDA as well as [123I]-MIBG specifically target catecholamine synthesis, storage, and

secretion pathways, and both enter the cell via the norepinephrine transporter (21, 22). In this

study, [18F]-FDA had a low lesion-based detection rate of 51.9% (CI 46.1% to 57.7%), which

might be explained by tumor dedifferentiation associated with loss of the norepinephrine

transporter in these patients. This is supported by the reported [123I]-MIBG negativity of more

than 50% of patients in SDHB mutation-associated PHEOs/PGLs (12). Six of the patients in our

study had undergone [123I]-MIBG-scintigraphy with a very low lesion detection rate of 18.7%

(CI 12.0% to 27.9%), but this result was most likely biased by the small patient cohort and the

heavy disease burden of our patient population.





[18F]-FDOPA targets cells via the amino acid transporter system (23) and has

demonstrated excellent results in patients with SDHx mutation-related head and neck PGLs (24).

However, the lesion-based sensitivity of [18F]-FDOPA in SDHB-related PHEOs/PGLs outside

the head and neck regions has been shown to be poor in a previous study (25). The detection rate

in our study reached 61.4% (CI 55.6% to 66.9%).

[18F]-FDG is a sensitive but non-specific radiopharmaceutical that enters the cell via

glucose transporters (GLUT) (26). Its accumulation is related to increased glucose metabolism as

seen in many different types of tumors (26). In SDHB-related metastatic PGLs, its high

sensitivity has been well documented (27-29). Higher standardized uptake values (SUV)

compared to sporadic and other hereditary PHEO/PGL are also reported, accompanied by an

upregulation of hexokinases 2 and 3 (30). Further, it is known that a mutation in the succinate

dehydrogenase complex II subunit B can lead to a downregulation or loss of succinate

dehydrogenase enzyme activity in the Krebs cycle, resulting in an upregulation of hypoxic

angiogenetic pathways via HIFs (6), which force tumor cells to shift from oxidative

phosphorylation to aerobic glycolysis (Warburg effect) (31). Currently, [18F]-FDG PET/CT is

recommended as the functional imaging technique of choice for patients with metastatic

PHEOs/PGLs, including their follow-up and assessment of treatment-related responses (20, 32).

In this study, we found a lesion-based detection rate of 85.8% (CI 81.3% to 89.4%) for [18F]-

FDG PET/CT.

With a lesion-based detection rate of 98.6% (CI 96.5% to 99.5%), [68Ga]-DOTATATE

PET/CT was significantly superior to all other functional imaging modalities in this study.

[68Ga]-DOTATATE, which is known to have an approximately 10-fold higher affinity for

SSTR2 than [68Ga]-DOTATOC (which also has high affinity to SSTR5) and an approximately





100-fold higher affinity for SSTR2 than [111In]-DTPA-octreotide (14), has already shown

excellent results in the imaging of SSTR2 expressing gastroenteropancreatic NETs (33), and

PHEOs/PGLs are also known to overexpress predominantly SSTR2 (13). A recent study also

demonstrated an increased expression of SSTR2A and SSTR3 in PHEOs/PGLs with SDH

deficiency (16), which also supports the approach of SSTR imaging and treatment in these

tumors. Until now, there have only been a few small and heterogeneous studies and case reports

on imaging of PHEOs/PGLs with DOTA-analogues. These have shown high sensitivities of

[68Ga]-DOTATATE and [68Ga]-DOTATOC PET/CT, approaching or reaching 100% (17, 34).

Besides its diagnostic value, [68Ga]-DOTATATE PET/CT can be used to determine

which patients may benefit from PRRT, which would be a desirable new treatment option for

these patients (7, 8). While PRRT has not been specifically evaluated in SDHB-related

PHEOs/PGLs yet, it has already been shown to lead to longer progression-free survival, mainly

in gastroenteropancreatic NETs (18) but also in other metastatic NETs, including PHEOs/PGLs

(35). Unfortunately, PRRT is not approved by the United States Food and Drug Administration

at present. In the meanwhile, the high sensitivity of [68Ga]-DOTATATE PET/CT in SDHB-

related metastatic PHEO/PGL suggests that these patients can be treated with cold SSTR

analogs, including sandostatin LAR, lanreotide, or others. Although this approach has not yet

been evaluated in PHEOs/PGLs, results using lanreotide in gastroenteropancreatic NETs (36)

and individual reports of octreotide treatment in patients with head and neck PGLs support this

approach (37, 38). This could also be extremely useful for patients in whom the location or

extension of a PHEO/PGL lesion(s) (especially skull base) cannot be accessed by any surgical

approach.

The phenomenon of additional lesions appearing with [68Ga]-DOTA-analogues PET/CT





that were not seen by other imaging studies has been reported before (15, 17). Since histologic

proof of these lesions in our study was not possible, these lesions have to be discussed as false

positive lesions. On the other hand, there are also studies that have reported histological

confirmation of SSTR-positive tumor tissue in such cases, which led to a treatment change in up

to 60% of patients (39).

Last, the high detection rate of [68Ga]-DOTATATE PET/CT in these patients also

suggests that the high malignant potential and presumed dedifferentiation of metastatic

PHEOs/PGLs in SDHB mutations apparently do not lead to a significant loss of SSTR

expression. This is supported by the increased SSTR2A and SSTR3 expression, which was found

in SDH-deficient tumors (16). Recently, SSTR expression with positive [68Ga]-DOTATOC

PET/CT was also shown in patients with undifferentiated Epstein-Barr virus-related

nasopharyngeal cancer (40). This also indicates that a loss in tumor differentiation is not

necessarily combined with a loss in SSTR expression.

In the current guidelines, which do not yet take PET imaging with [68Ga]-DOTA-peptides

into consideration, [18F]-FDG is recommended as first-line functional imaging of SDHB-related

PHEO/PGL (20). However, our results indicate that [68Ga]-DOTATATE PET/CT may have an

incremental diagnostic value in the detection of disease sites, which could have an impact on

patient care. Therefore, we believe that future guidelines may modify the recommendations in

favor of using [68Ga]-DOTA-peptides, especially if confirming results from a larger number of

patients, sporadic PHEO/PGL patients, and other PHEO/PGL genotypes are made available.

In clinical settings such as the evaluation of treatment response after systemic

radionuclide therapy or chemotherapy, the use of [68Ga]-DOTATATE PET/CT is still unclear

and has to be evaluated. In clinical settings of doubtful CT/MRI results, [68Ga]-DOTATATE





might also be helpful, although potential false positive results could occur. The more specific

functional imaging studies like [18F]-FDOPA and [18F]-FDA PET/CT seem to harbor a higher

risk for false negative results. Last, [18F]-FDOPA PET/CT and especially [18F]-FDA PET/CT are

of limited availability, whereas for [68Ga]-DOTATATE PET/CT, we believe broader clinical

availability can be expected in the future.

Our study was subject to certain limitations, including the relatively small number of

patients and possible bias related to our chosen reference test. Based on this imaging comparator,

combined positive findings in functional and/or anatomical imaging studies on one hand cannot

fully exclude false positive results (e.g., possible positive lesions in [68Ga]-DOTATATE

PET/CT, [18F]-FDG-PET/CT, and/or CT/MRI related to inflammation or possible positive

lesions in [68Ga]-DOTATATE PET/CT, [18F]-FDOPA PET/CT, and/or CT/MRI related to

different neuroendocrine tumors). On the other hand, true positive findings, which only appear in

one imaging modality, e.g. CT/MRI, would have been counted as false positive in our setting.

In conclusion, although [18F]-FDG PET/CT is currently recommended as the functional

imaging technique of choice in SDHB-related PHEOs/PGLs and our study is subject to certain

limitations, we believe that our results may indicate a preference for [68Ga]-DOTATATE

PET/CT in these patients, particularly in the detection of progressive metastatic disease,

additional disease sites, and even early detection of metastatic disease. [68Ga]-DOTATATE

PET/CT can also be used to help determine the eligibility of patients for PRRT, a new and

hopefully soon to be available treatment option. The utility of [68Ga]-DOTATATE PET/CT in

other genotypes, sporadic PHEO/PGL, or for treatment monitoring should be evaluated soon.





ACKNOWLEDGEMENTS

We would like to acknowledge the technical assistance of Joan Nambuba and Robert A.

Wesley in the production of this manuscript.

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TABLES

Table 1: Individual patient characteristics.

Pt. # Sex SDHB mutation Age (d)

Age (s) LOP

Hyper secretion TTM LOM Treatment

1 m

c.725G>A,

p.Arg242His 20 34 R skull None 12 B RT skull

2 f

c.688C>T,

p.Arg230Cys 22 25 L carotid body None 0 B, Lu, Me Res primary

3 m

c.418G>T,

p.Val140Phe 10 20

Aortic

bifurcation

NE, NMN,

DA 0 B, A/P Res primary

4 m

c.689G>A,

p.Arg230His 52 52 R para-adrenal NE, NMN 0 B

RT skull

Res primary

5 f

c.343C>T,

p.Arg115X 32 43

Urinary

bladder NE, NMN 3 B, Lu, A/P

Res primary,

CVD

6 f

c.689G>A,

p.Arg230His 28 50 L carotid body None 20 Lu, Li

Res primary,

CVD

7 f

c.136C>T,

p.Arg46X 19 24

R glomus

jugulare None 0 B, Ne

Res primary, RT

skull

8 m

c.200+33G>A,

p.Glu228Glyfsx27 47 59 L para-adrenal DA, MTT 3

Me, Ne,

A/P Res. primary

9 m

c.136C>T,

p.Arg46X 45 46

urinary

bladder NE, NMN, 0 Lu, B Res primary

10 m

c.136C>T,

p.Arg46X 25 37 R mediastinal None 0 Lu

Res primary,

CVD

11 m c.72+1G>T 54 60 R para-adrenal NE, NMN 0

Lu, Me,

A/P, B

Res primary ,

MIBG

12 f Exon 1 deletion 49 55

Aortic

bifurcation

NE, NMN,

DA, MTT 0

Ne, Me,

A/P

Res primary,

MIBG

13 m

c.330_331del,

p.Leu111SerfsX7 10 23 L adrenal NE, NMN 0

B, Lu, Ne,

A/P, Li Res primary

14 m

c.268C>T,

p.Arg90X 11 26 R adrenal None 8 B, Lu, Ne

Res primary,

MIBG

15 m Exon 1 deletion 34 41 R para-adrenal

NMN, DA,

MTT 5 Me, B

Res primary

16 m

c.137G>A,

p.Arg46Gln 19 36 L pelvis NE, NMN,

DA, MTT 13

B, Lu, Ne,

A/P

Res primary,

MIBG, CVD

17 f

c.541-2A>G,

splice site

mutation

36 54 L carotid body NE, NMN,

DA, MTT 8 B Res primary





Abbreviations: Age (d), age at diagnosis; age (s), age at study; A/P, abdomen/pelvis; B, bones; CVD, chemotherapy

with CVD; DA, dopamine; f, female, L, left; LOM, location of metastases; LOP, location of primary; Lu, lungs; m,

male; Me, mediastinum, MIBG, 131I-MIBG treatment; Mtt, methoxytyramine, Ne, neck; NE, norepinephrine; NMN,

normetanephrine; no, number; Pat., patient; R, right; Res, surgical resection; RT, radionuclide therapy; TTM, time to

metastases (years).

Table 2: Number of identified lesions in [68Ga]-DOTATATE, [18F]-FDA-, [18F]-FDOPA-, [18F]-

FDG-PET/CT, and CT/MRI compared to lesions identified by the imaging comparator.

Table 3: Detection rate (%) and 95% CI (%) for [68Ga]-DOTATATE, [18F]-FDA-, [18F]-

FDOPA-, [18F]-FDG-PET/CT, and CT/MRI.

Lesions [68Ga]-DOTATATE [18F]-FDG [18F]-FDOPA [18F]-FDA CT/MRI

All compartments 285/289 248/289 175/285 148/285 245/289

Mediastinum 65/65 57/65 39/65 39/65 55/65

Lungs 62/63 45/63 45/63 18/63 62/63

Abdomen 43/43 40/43 31/43 19/43 33/43

Liver 5/5 3/5 4/5 0/5 5/5

Bone 95/98 91/98 41/94 57/94 82/98

Detection rate [68Ga]-DOTATATE [18F]-FDG [18F]-FDOPA [18F]-FDA CT/MRI

All compartments 98.6 (96.5 to 99.5) 85.8 (81.3 to 89.4) 61.4 (55.6 to 66.9) 51.9 (46.1 to 57.7) 84.8 (80.0 to 88.5)

Mediastinum 100 (94.4 to 100) 87.7 (77.6 to 93.6) 60.0 (47.9 to 71.0) 60.0 (47.9 to 71.0) 84.6 (73.9 to 91.4)

Lungs 98.4 (92.5 to 99.7) 71.4 (59.3 to 81.1) 71.4 (59.3 to 81.1) 28.6 (18.9 to 40.7) 98.4 (91.5 to 99.7)

Abdomen 100 (91.8 to 100) 93.0 (81.4 to 97.6) 72.1 (57.3 to 83.3) 44.2 (30.4 to 58.9) 76.7 (62.3 to 88.7)

Liver 100 (56.5 to 100) 60.0 (23.1 to 88.2) 80.0 (37.6 to 96.4) 0% (0.0 to 43.5) 100 (56.5 to 100)

Bone 96.9 (91.4 to 99.0) 92.9 (86.0 to 96.5) 43.6 (34.0 to 53.7) 60.6 (50.5 to 69.9) 83.7 (75.1 to 89.7)





FIGURES

Figure 1: Identified lesions (positive columns) and missed lesions (negative columns) for

CT/MRI, [18F]-FDG, [68Ga]-DOTATATE, [18F]-FDOPA, and [18F]-FDA PET/CT.

Figure 2: 24-year-old female patient with metastatic paraganglioma and SDHB mutation, first

diagnosed with left carotid body tumor, lung and bone metastases in 2011. [68Ga]-DOTATATE

PET (A) demonstrated additional lung and bone lesions (arrows), compared to [18F]-FDG PET

(B) and [18F]-FDOPA PET (C). [18F]-FDA PET (D) and [123I]-MIBG scintigraphy (not shown)

were negative.




Bone Abdomen Lungs

All compartments Mediastinum

55 57 65

39 39

-10 -8 0 -24 -24

62

45

62

45

18

-1 -18 -1 -18 -45

33 40 43

31

19

-10 -3 0 -12 -24

245 248 285

175 148

-44 -41 -4 -110 -137

82 91 95

41 57

-16 -7 -3 -53 -27

Figure 1




A B C D

Figure 1Figure 2




Published OnlineFirst April 14, 2015.Clin Cancer Res Ingo Janssen, Elise M Blanchet, Karen Adams, et al. metastatic pheochromocytoma and paragangliomaimaging modalities in the localization of SDHB-associated Superiority of [68Ga]-DOTATATE PET/CT to other functional

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